PROJECT SUMMARY This new R01 aims to study the effects of selective serotonin reuptake inhibitor (SSRI) antidepressant medication use by women in pregnancy on their offspring?s brain and cognitive development in the first two years of life. Fetal exposure to antidepressants is a critical public health question because prescriptions of SSRIs to pregnant women have increased 4-8-fold over the last 30 years, yet their impact on fetal neurodevelopment remains unknown. Although considered safe and effective for the mother, SSRIs readily cross the placenta and into the fetal brain, potentially altering the important neurotropic role of 5-HT during the fetal period. Whether this fetal exposure translates to long-term effects on the offspring remain unclear. The choices facing physicians and pregnant women are similarly unclear, as discontinuing SSRI and leaving maternal depression untreated can have deleterious consequences for both mother and child. To address these questions more definitively, we have partnered with the University of Sherbrooke (Quebec, Canada) to develop a new birth cohort and test the effects of SSRI and maternal depression exposures on offspring neurodevelopment. We will enroll pregnant women with (n=250) and without (n=125) a depressive disorder in their first trimester, and assess the course of their depressive symptoms and medication usage over the remaining pregnancy. By conclusion of pregnancy, we will know whether the infant was exposed to SSRIs; the quantity (dose) and timing (trimester) of that exposure; and the length and severity of maternal depression during the concurrent period. We will perform an MRI scan and EEG assessment when the infant is 1 month old, and then longitudinally follow the offspring with repeated EEG, as well as behavioral measures of emotion regulation through the first two years of life to test whether any abnormalities in brain structure or connectivity identified at 1 month have developmental consequences. We will also examine the influence of the post-natal family environment, monitoring parental (maternal and paternal) depression symptoms monthly, and conducting two in-home assessments of family. These detailed longitudinal assessments will allow our study to more definitively separate effects of medication from depression exposure, and to characterize the influence of the family environment on gestational SSRI effects. If funded, we will form the largest cohort testing brain and behavioral outcomes of fetal antidepressant exposure to date. Findings will be clinically informative regardless of their direction. If we find significant brain or behavioral problems in offspring who were fetal exposed to antidepressants, women can be directed to other medication and non-medication treatments for depression that may be safer for mother and child. And if we find no adverse effects, then this will provide reassurance for the safe use of SSRIs, and potentially increase compliance as well.